Chemotherapy with etoposide and cisplatin or carboplatin

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1 Brief Report A Multicenter, Open-Label, Randomized Phase II Controlled Study of rh-endostatin (Endostar) in Combination with Chemotherapy in Previously Untreated Extensive-Stage Small-Cell Lung Cancer Shun Lu, MD,* Lu Li, MD, Yi Luo, MD, Li Zhang, MD, Gang Wu, MD, Zhiwei Chen, MD,* Cheng Huang, MD, Shuliang Guo, MD,# Yiping Zhang, MD,** Xiangqun Song, MD, Yongfeng Yu, MD,* Caicun Zhou, MD, Wei Li, MD, Meilin Liao, MD,* Baolan Li, MD, Liyan Xu, MD, Ping Chen, MD, Chunhong Hu, MD, and Chengping Hu, MD## Background: Based on promising efficacy in a single-arm study, a randomized phase II trial was designed to compare the efficacy and safety of adding rh-endostatin (Endostar) to first-line standard etoposide and carboplatin (EC) chemotherapy for treatment of extensivestage small-cell lung cancer. Methods: One hundred forty Chinese patients with pathologically confirmed, extensive-stage small-cell lung cancer were randomly assigned to EC alone or rh-endostatin + EC for 4 6 cycles, followed by single-agent rh-endostatin until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, Objective response rate (ORR), and quality of life. *Department of Oncology, Shanghai Lung Cancer Center, Chest Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China; Department of Thoracic Cancer, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Department of Medical Oncology, Hunan Provincial Tumor Hospital, Changsha, Hunan, China; Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China; The Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Medical Oncology, Fujian Provincial Tumor Hospital, Fujian Medical University Educational Hospital, Fuzhou, China; #Department of Respiratory Medicine, The First Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing, China; **Chemotherapy Center of Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China; Department of Chemotherapy, Affiliated Tumor Hospital, Guangxi Medical University, Guangxi, China; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China; Cancer Center of the First University Hospital, Jilin University, Changchun, China; Department of General, Beijing Chest Hospital, Beijing, China; Department of Oncology, Second Xiangya Hospital of Central-South University, Changsha, China; and ##Department of Respiratory Disease, Xiang-ya Hospital, Central Southern University, Hunan, Changsha, China. Disclosure: The authors declare no conflict of interest. Address for correspondence: Shun Lu, MD, Department of Oncology, Shanghai Lung Cancer Center, Chest Hospital Affiliated to Shanghai Jiaotong University, 241 West Huaihai Road, Xuhui District, Shanghai , China. lushun1964@126.com DOI: /JTO ISSN: /15/ Results: Median PFS was 6.4 months with rh-endostatin + EC and 5.9 months with EC (hazard ratio 0.8 [95% confidence interval ]). PFS was significantly higher with rhendostatin + EC than with EC (hazard ratio 0.4 [ ; p = 0.020]) in female. Median overall survival was similar in both groups (12.1 versus 12.4 months, respectively [p = 0.82]). ORR was higher in the rh-endostatin + EC group (75.4%) than in the EC group (66.7%) (p = 0.348). The efficacy of rh-endostatin + EC relative to that of EC was reflected by greater improvements in patient-assessed quality of life scores after 4 and 6 weeks of treatment. There was no difference between each regimen in the incidence of nonhematological or Grade III IV hematological toxicities. Conclusions: Addition of rh-endostatin to EC for the treatment of extensive-stage small-cell lung cancer had an acceptable toxicity profile, but did not improve overall survival, PFS, and ORR. Key Words: Etoposide, Carboplatin, Rh-endostatin, Extensive-stage small-cell lung cancer, Survival. (J Thorac Oncol. 2015;10: ) Chemotherapy with etoposide and cisplatin or carboplatin has been the standard treatment for small-cell lung cancer (SCLC) over the last 30 years. These regimens are associated with response rates of 50 60% with a very short median progression-free survival (PFS) of 2 6 months and median survival times of 7 11 months. 1,2 Rh-endostatin (Endostar) is a novel recombinant human endostatin, and was approved for non SCLC (NSCLC) in China in It has been shown to improve overall survival (OS) and PFS when combined with first line chemotherapy in patients with advanced NSCLC. 3,4 A single-arm phase II study of cisplatin/ etoposide plus Rh-endostatin in 33 patients with extensivestage SCLC reported a median PFS of 5 months, median OS of 11.5 months, and objective response rate (ORR) of 69.7%. 5 This study aimed to assess the efficacy and safety of rh-endostatin in combination with first-line standard chemotherapy of etoposide plus carboplatin in the treatment of extensivestage SCLC. 206 Journal of Thoracic Oncology Volume 10, Number 1, January 2015

2 Journal of Thoracic Oncology Volume 10, Number 1, January 2015 Extensive-Stage Small-Cell Lung Cancer MATERIAL AND METHODS Patients and Eligibility This study enrolled 140 patients with histologically or cytologically confirmed extensive-stage, treatment-naive SCLC at 14 medical institutions in China between July 2009 and Aug All patients were between 18 and 75 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2 and expected survival of more than 12 weeks. Other inclusion/exclusion/withdrawal criteria were standard for phase II studies (see Supplemental Digital Content, com/jto/a700). Details on informed consent, ethical clearance, and trial registration are also provided in the Supplemental Digital Content ( Study Design Patients were randomly assigned to the following two treatment groups: etoposide and carboplatin (EC) group, and EC + rh-endostatin group. The EC + rh-endostatin group received a 3- to 4-hour intravenous infusion of rhendostatin (7.5 mg/m 2 once daily, equivalent to U/ m 2 of human endostatin; Shandong Simcere-Medgenn Bio- Pharmaceutical Co., Ltd., Yantai, China) on Days 1 to 14 of each 21-day cycle. Etoposide was administered (60 mg/m 2, Qilu Pharmaceutical Co., Ltd., Jinan, China) on days 1 to 5, and carboplatin (Bristol-Myers Squibb S.r.I., Sermoneta, Italy) was administered at a target area under the concentration curve of 5 mg/ml/min on day 1 of each cycle. All patients received four to six 21-day cycles. After four to six cycles, patients who did not display disease progression continued to receive rh-endostatin (7.5 mg/m 2 once daily) on days 1 to 14 of each 21-day cycle until tumor progression, unacceptable toxicity, discontinuation from study, or death. Patients allocated to the EC group received etoposide (60 mg/m 2 ) on days 1 to 5 and carboplatin at an area under the concentration curve of 5 mg/ml/min on day 1 of each cycle. Study Endpoints The primary study endpoint was assessment of PFS. The secondary endpoints included OS, ORR (sum of complete and partial remission rates), and quality of life (QOL). Tumors were assessed as per RECIST 1.0. Response to treatment was assessed every two cycles by computed tomography and confirmed at 21 days after treatment termination. All endpoints were assessed by an independent review committee that included experienced and trained medical and oncological professionals. Statistical Considerations Data are presented as numbers and percentages, medians and ranges, or means and standard deviations (±SD). Intergroup comparisons were performed using Student s t test, Wilcoxon rank-sum test, and Fisher s exact test, as appropriate. Efficacy data are presented for the intent-to-treat patient population. Survival was censored at the last tumor assessment. Median PFS and OS were estimated by Kaplan Meier methodology, and they are reported with 95% confidence intervals. Logrank test was used for comparison. A Cox proportional hazards model stratified by ECOG performance status (0 1 versus 2) and gender (male versus female) was used to obtain a point estimate of hazard ratio (HR) for rh-endostatin plus chemotherapy compared with chemotherapy alone. The per protocol analysis included all patients who received all drugs as per study protocol, and who did not use any forbidden drugs, did not deviate from study protocol, completed all assessments and did not withdraw from the study, except because of death. All analyses were conducted using SAS 9.0 (SAS Institute, Cary, NC). All probability tests were two-tailed, and p values less than 0.05 were considered statistically significant. RESULTS Subjects Characteristics Of the 140 patients enrolled, 2 withdrew consent after randomization; 69 patients were in the rh-endostatin + EC group, and 69 patients were in the EC control group. The study flow chart is shown in Figure 1. Table 1 depicts the baseline characteristics of enrolled patients. Efficacy Progression-free survival Follow-up analysis of patients by August 31, 2012, revealed disease progression or death in 58 patients (84.1%) receiving rh-endostatin + EC and in 56 patients (81.2%) receiving EC alone. Median PFS was 6.4 months for the rhendostatin + EC group, and 5.9 months for the EC group (p = 0.213). PFS at 6 months was 59.3% in the rh-endostatin + EC group and 46.6% in the EC group (Fig. 2). Subgroup analysis showed that PFS in female patients (n = 25) was significantly higher with rh-endostatin + EC (7.3 months) compared with EC alone (3.9 months) (p = 0.020). The corresponding HR in female patients was 0.4 ( ) (Fig. 3). Objective remission rate The corresponding ORR (95% confidence interval) was 75.4% ( %) with rh-endostatin + EC and 66.7% ( %) with EC, but the difference was not statistically significant (p = 0.348). However, analysis of the per-protocol population showed that the ORR was significantly higher in patients treated with rh-endostatin + EC (86.7%; range: %) than in the EC group (71.0%; range: %; p = 0.046) (Table 2). Overall survival Median OS among patients receiving rh-endostatin + EC (12.1 months) was similar to that among patients receiving EC alone (12.4 months; p = 0.812). The 1-year survival rate was 50.0% with rh-endostatin + EC and 54.6% with EC. The corresponding HR (95% confidence interval) was 1.0 ( ). Similar results were obtained in the per-protocol population (HR: 1.0 [ ]) (Fig. 4). Lung cancer symptom scale QOL scores Improvements in patient-assessed QOL were significantly greater after 4 and 6 weeks of treatment with rh-endostatin + EC compared with EC (Fig. 5). 207

3 Lu et al. Journal of Thoracic Oncology Volume 10, Number 1, January 2015 Figure 1. Study flowchart and patient disposition. EC, etoposide and carboplatin; ITT, intention-to-treat. Safety The most common non-hematological adverse events (AEs) in both groups included nausea, anorexia, elevated alanine aminotransferase levels, elevated aspartate aminotransferase levels, vomiting, and weakness (Table 3). In the rh-endostatin + EC group, one patient had elevated blood pressure, another had nodal tachycardia and atrial premature beats, and another reported palpitation. These events were all mild in intensity and were not reported in the EC group. II study comparing rh-endostatin + first-line EC chemotherapy with EC chemotherapy alone in patients with advanced stage SCLC. The median PFS with rh-endostatin + EC was observed to be slightly longer than with EC alone, but without DISCUSSION Rh-endostatin has been shown to have clinical activity against NSCLC. 3,4 This study reports the findings of a phase Table 1. Baseline Characteristics Characteristics rh-endostatin + EC p Value Age (years) Mean (SD) 57.7 (8.49) 58.2 (7.84) Median (range) 56.0 (40 76) 59.0 (36 73) Gender Male 56 (81.2%) 57 (82.6%) Female 13 (18.8%) 12 (17.4%) ECOG 0 12 (17.4%) 13 (18.8%) (75.4%) 55 (79.7%) 2 5 (7.2%) 1 (1.4%) ECOG, Eastern Cooperative Oncology Group. Figure 2. Progression-free survival (PFS) curve. EC, etoposide and carboplatin. 208

4 Journal of Thoracic Oncology Volume 10, Number 1, January 2015 Extensive-Stage Small-Cell Lung Cancer Figure 3. Subgroup analysis of progression-free survival curve. EC, etoposide and carboplatin; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; CI, confidence interval. significant difference. The results were similar to those of other studies of bevacizumab, paclitaxel, or irinotecan in combination with rh-endostatin. 6 9 In as unplanned subgroup analysis, data suggest that Rh-endostatin + EC resulted in a significant PFS benefit over EC chemotherapy alone among female patients with SCLC. This is an interesting finding, since it is generally recognized that the incidence of lung cancer is increasing among female patients, 10 but further studies are necessary to confirm this finding. Nevertheless, it has also been reported that female gender is a good prognostic factor for extensive-stage SCLC, and that women with both NSCLC and SCLC survive longer than men. 10,11 In this study, there was no significant difference in OS in patients allocated to rh-endostatin + EC and those receiving EC alone. These survival rates were comparable to those observed with EC + bevacizumab or paclitaxel or irinotecan. 1,6 9 The negative results observed in this study were comparable to the results from studies of rh-endostatin + EC in patients with advanced SCLC, 5,12 and to the results of adding rh-endostatin to paclitaxel and carboplatin in NSCLC. 13 Promising results were obtained using sunitinib maintenance therapy, 14 and the right choice of drug combination might be essential to obtain positive results from rh-endostatin. The difference of ORR between the two groups was not statistically significant, while another study showed an improved ORR in patients receiving rh-endostatin. 12 However, when considering the per-protocol population only, ORR was significantly higher with rh-endostatin + EC (86.7%) than with EC (71.0%; p = 0.046). Nevertheless, when considering the whole population or the per protocol population, ORR achieved with rh-endostatin + EC was higher than that reported for EC + bevacizumab or irinotecan, and was comparable to Table 2. Remission Rates Category rh-endostatin + EC Number of Patients p Value Complete remission 2 (2.9%) 1 (1.4%) Partial remission 50 (72.5%) 45 (65.2%) Stable disease 5 (7.2%) 12 (17.4%) Progressive disease 3 (4.3%) 6 (8.7%) No assessment 9 (13.0%) 5 (7.2%) Objective response rate 75.4% ( %) 66.7% ( %) a a Fisher s exact test. Objective response rate is the sum of the complete and partial remission rates. Figure 4. Overall survival (OS) curve. EC, etoposide and carboplatin. 209

5 Lu et al. Journal of Thoracic Oncology Volume 10, Number 1, January 2015 Figure 5. Lung cancer symptom score quality of life assessments. Data are expressed as median. *p < EC, etoposide and carboplatin; QOL, quality of life. that reported for EC + irinotecan. 1,6 9 Randomized studies should be performed to directly compare these drugs with rh-endostatin. The efficacy of rh-endostatin + EC relative to that of EC alone was reflected by greater improvements in patientassessed lung cancer symptom scale QOL scores after 4 and 6 weeks of treatment. This finding is in line with a previous study showing improved QOL with rh-endostatin plus carboplatin in the early stages of treatment of advanced NSCLC. 13 The tolerability of rh-endostatin + EC was comparable to that reported in another phase II study. 5 No cases of severe cardiovascular toxicity were reported, and there were no hematological AEs. However, improvements in QOL alone, without improvements in OS or PFS, are not sufficient to adopt a new treatment. The better QOL observed in this study might be the result of more frequent visits to the hospital for the patients receiving rh-endostatin on a daily basis. However, the impact Table 3. Incidence of Adverse Reactions All Grades, N (%) Grades III to V, N (%) Adverse Reaction Rh-endostatin + EC p Value Rh-endostatin + EC ( = 69) p Value Hematopoietic system Leukopenia 62 (89.9%) 63 (91.3%) (29.0%) 15 (21.7%) Neutropenia 61 (88.4%) 56 (81.2%) (55.1%) 27 (39.1%) Hemoglobin 55 (79.7%) 53 (76.8%) (15.9%) 7 (10.1%) Thrombocytopenia 36 (52.2%) 34 (49.3%) (18.8%) 13 (18.8%) Anemia 10 (14.5%) 4 (5.8%) (1.4%) 2 (2.9%) Decreased absolute lymphocytes 2 (2.9%) 3 (4.3%) (1.4%) 1 (1.5%) Decreased lymphocyte counts 0 (0%) 3 (4.3%) (0%) 1 (1.5%) Myelosuppression 1 (1.4%) 0 (0%) (1.4%) 0 (0%) Digestive system Nausea 21 (30.4%) 20 (29.0%) (1.4%) 0 (0%) Anorexia 18 (26.1%) 13 (18.8%) (1.4%) 0 (0%) Aminopherase 16 (23.2%) 12 (17.4%) (0%) 1 (1.5%) Vomiting 9 (13.0%) 10 (14.5%) (1.4%) 0 (0%) Constipation 3 (4.3%) 1 (1.4%) (0%) 0 (0%) N/A Hyperbilirubinemia 3 (4.3%) 1 (1.4%) (0%) 0 (0%) N/A Diarrhea 1 (1.4%) 1 (1.4%) (1.4%) 1 (1.5%) Abdominal distension 2 (2.9%) 0 (0%) (1.4%) 0 (0%) Fecal occult blood 1 (1.4%) 0 (0%) (0%) 0 (0%) N/A General disorders Weakness 6 (8.7%) 5 (7.2%) (2.9%) 0 (0%) Alopecia 6 (8.7%) 4 (5.8%) (0%) 0 (0%) N/A Fever 1 (1.4%) 1 (1.4%) (0%) 0 (0%) N/A Infection 1 (1.4%) 0 (0%) (0%) 0 (0%) N/A Agranulocytic fever 1 (1.4%) 0 (0%) (0%) 0 (0%) N/A Laboratory abnormalities LDH 1 (1.4%) 2 (2.9%) (0%) 0 (0%) N/A Hypocalcemia 1 (1.4%) 0 (0%) (0%) 0 (0%) N/A Electrolyte disturbance 1 (1.4%) 0 (0%) (0%) 0 (0%) N/A LDH, lactate dehydrogenase; N/A, not applicable. 210

6 Journal of Thoracic Oncology Volume 10, Number 1, January 2015 Extensive-Stage Small-Cell Lung Cancer of the 3- to 4-hour daily infusions for 14 consecutive days might counteract this benefit. Despite the relatively long median follow-up of 20 months among patients with advanced stage SCLC, the relatively small sample size may have limited the power of the study to detect statistically significant differences between treatment regimens. In addition, the patients were selected from 14 different centers across China. While this strategy may make the study more applicable to a real-life setting, differences in patient procedures between the centers may have influenced the study endpoints. Finally, tumor markers were not measured. CONCLUSIONS The preliminary findings in a small population of patients with advanced SCLC suggest that the addition of rhendostatin to EC for the treatment of extensive-stage SCLC had an acceptable toxicity profile, but did not improve OS, PFS, or ORR. Hence, the use of rh-endostatin in SCLC remains exploratory. ACKNOWLEDGMENTS The authors thank the physicians, nurses, pathologists, and laboratory technicians who were involved in this study. The authors also appreciate the participation of all the patients and their families for their support. This work was supported by grants from Simcere Pharmaceutical Co., China, International S&T Cooperation Program of China (2012DFG31320), Foundation for Leaders of Disciplines in Science of Shanghai (13XD ), Science and Technology Commission Foundation of Shanghai (06DZ19501), and National High Technology Research and Development Program of China (2012AA02A502). REFERENCES 1. Noda K, Nishiwaki Y, Kawahara M, et al; Japan Clinical Oncology Group. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346: Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Determinants of improved outcome in small-cell lung cancer: an analysis of the 2,580-patient Southwest Oncology Group data base. J Clin Oncol 1990;8: Wang J, Sun Y, Liu Y, et al. Results of randomized, multicenter, double-blind phase III trial of rh-endostatin (YH-16) in treatment of advanced non-small cell lung cancer patients. Zhongguo Fei Ai Za Zhi 2005;8: Rong B, Yang S, Li W, et al. Systematic review and meta-analysis of Rh-endostatin (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer. World J Surg Oncol 2012;10: Zhou ZT, Zhou FX, Wei Q, et al. Phase II study of cisplatin/etoposide and rh-endostatin for extensive-stage small-cell lung cancer. Cancer Chemother Pharmacol 2011;68: Horn L, Dahlberg SE, Sandler AB, et al. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group Study E3501. J Clin Oncol 2009;27: Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011;29: Niell HB, Herndon JE 2nd, Miller AA, et al; Cancer and Leukemia Group. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial J Clin Oncol 2005;23: Lara PN Jr, Natale R, Crowley J, et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009;27: Svensson G, Ewers SB, Ohlsson O, Olsson H. Prognostic factors in lung cancer in a defined geographical area over two decades with a special emphasis on gender. Clin Respir J 2013;7: Kuo YH, Lin ZZ, Yang YY, et al. Survival of patients with small cell lung carcinoma in Taiwan. Oncology 2012;82: Chen JH, Luo YZ, Zhou WW, et al. Recombinant human endostatin combined carboplatin plus etoposide for advanced small-cell lung cancer ASCO Annual Meeting. 2014:e Han B, Xiu Q, Wang H, et al. A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of paclitaxel-carboplatin alone or with rh-endostatin for advanced non-small cell lung cancer. J Thorac Oncol 2011;6: Ready N, Pang H, Gu L, et al. Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small cell lung cancer: a randomized, placebo controlled phase II study CALGB (ALLIANCE) ASCO Annual Meeting. 2013: